Researchers at UC Davis have identified a critical immune system malfunction in children with autism: they have fewer regulatory T cells, the immune system's natural 'brakes' that prevent excessive inflammation. Two groundbreaking studies suggest that restoring these cells could reduce both inflammation and behavioral challenges associated with autism, offering a completely new therapeutic approach .

What Are Regulatory T Cells and Why Do They Matter?

Regulatory T cells, often called Tregs, function as the immune system's peacekeepers. When your immune system detects a threat, it launches an inflammatory response to protect you. But without Tregs to dial down that response, inflammation can spiral out of control, damaging healthy tissue and triggering symptoms. In children with autism, researchers found that these critical cells are not only reduced in number but also genetically altered in ways that make them less effective .

The connection between immune dysfunction and autism has been building for years. Previous research showed that people with autism often have higher levels of inflammatory immune cells circulating in their blood, brain, and gut. These elevated inflammatory responses are frequently linked to greater behavioral support needs. Conversely, children with higher levels of Tregs tend to show improved behavioral outcomes. Yet until now, Tregs have remained largely understudied in autistic children, and their potential as a treatment target has been largely overlooked .

How Did Researchers Discover These Immune Differences?

The first study, published in the Journal of Neuroinflammation, examined Tregs in 36 children with autism and compared them to 18 typically developing children, all enrolled in the CHARGE study (Childhood Autism Risk from Genetics and Environment). Researchers analyzed both the number of Tregs and the genes these cells were using. The findings were striking .

Children with autism showed multiple immune abnormalities:

• Lower Treg counts: Autistic children had fewer Tregs overall compared to typically developing peers, with specific reductions depending on whether a child had gastrointestinal issues.
• Altered gene expression: Tregs from autistic children showed 213 differentially expressed genes, with 171 genes turned up and 42 turned down, suggesting the cells' identity and function were unstable.
• Metabolic dysfunction: The upregulated genes mainly helped cells reorganize and repair DNA, while downregulated genes involved in energy production were reduced, indicating the Tregs were struggling to function properly.
• GI-specific patterns: Children with autism and gastrointestinal problems had fewer Tregs capable of producing anti-inflammatory proteins, while those without GI issues had fewer Tregs capable of dividing after activation.

One consistent finding across both groups: having fewer Tregs was associated with more challenging behaviors in both typically developing children and children with autism .

"These differences in Treg populations may help explain the higher levels of inflammation seen in autism and could be linked to both gastrointestinal problems and certain behavioral traits. This data further supports the idea that the immune system plays an important role in autism in at least some individuals," explained Rachel Moreno, a postdoctoral fellow at the UC Davis MIND Institute and first author of the study.

Rachel Moreno, Postdoctoral Fellow, UC Davis MIND Institute

Can Boosting Tregs Actually Improve Autism Symptoms?

In a second study, also published in the Journal of Neuroinflammation, researchers tested whether increasing Tregs could actually reduce inflammation and behavioral challenges. They used a mouse model of maternal immune activation (MIA), where offspring develop autism-like behaviors. The team transferred healthy Tregs into these mice and tracked changes in tissues commonly inflamed in autism, including blood, brain, and gut .

The results were remarkable, though they revealed important sex differences. Male mice showed the most dramatic improvements after Treg treatment:

• Immune rebalancing: Treg treatment increased helpful Treg cells and reduced pro-inflammatory cells in both the spleen and gut, creating a healthier immune balance.
• Reduced inflammatory signals: Males produced fewer inflammatory cytokines, such as IL-17, after treatment, indicating a significantly calmer immune system.
• Brain-wide changes: Hundreds of genes in the cerebellum, frontal cortex, and hippocampus changed after Treg treatment, many related to brain development, immune activity, and autism-related conditions.
• Behavioral improvements: After Treg treatment, males showed improvements in self-grooming and socializing, two key behavioral domains affected in autism.

Female mice showed a more complex response. While they experienced improved social behavior after Treg treatment, they showed fewer changes in immune cells, modest impacts on gut and spleen cell types, and minimal changes in brain gene expression. Some inflammatory molecules decreased while others increased, suggesting a more nuanced immune response in females .

"Transferring Tregs reduced inflammation and improved brain and behavioral outcomes in the MIA model, with the most significant benefits seen in male mice. These results suggest that Treg therapy could be a promising approach for reducing inflammation and related impacts in conditions linked to maternal immune activation and neurodevelopmental conditions such as autism," stated Paul Ashwood, senior author of both studies.

Paul Ashwood, Professor, Department of Medical Microbiology and Immunology, UC Davis MIND Institute

What Does This Mean for Autism Treatment?

These findings open an entirely new therapeutic avenue. Rather than targeting individual symptoms, Treg-based therapies could address the underlying immune dysfunction that contributes to autism in at least some individuals. There is already growing interest in biological therapies for autism that specifically target Tregs, and these studies provide the first solid evidence that such approaches could work .

However, researchers acknowledge important limitations. The first study involved a relatively small sample size of 36 autistic children and 18 controls. In the second study, Treg transfer occurred at 10 weeks of age in mice, but transferring Tregs into younger mice when the immune and brain systems are still developing might be more relevant for understanding how this therapy could work in human infants and young children .

The sex differences observed in the mouse studies also raise important questions. If similar patterns hold in humans, Treg therapy might need to be tailored differently for boys and girls, a consideration that will require careful attention in future clinical trials.

Steps Researchers Are Taking to Develop Treg Therapy

• Expanding sample sizes: Future studies will need to include larger groups of autistic children to confirm these findings and better understand which individuals might benefit most from Treg therapy.
• Testing earlier interventions: Researchers plan to test Treg transfer in younger mice to determine whether earlier immune intervention could have even greater effects on brain development and behavior.
• Investigating sex-specific approaches: Scientists will examine whether Treg therapy needs to be customized for males and females based on the different immune responses observed in this study.
• Understanding the mechanism: Additional research will clarify exactly how Tregs influence brain development, gene expression in key brain regions, and the specific behavioral improvements seen in the studies.

This research was supported by multiple funding sources, including the National Institute of Child Health and Human Development, National Institutes of Mental Health, Department of Defense, Autism Speaks, and the Autism Research Institute, underscoring the significant scientific interest in this approach .

For families affected by autism, these studies represent a shift in how scientists think about the condition. Rather than viewing autism solely as a neurological disorder, researchers increasingly recognize it as a condition where immune system dysfunction plays a central role. By restoring immune balance through Treg therapy, scientists may be able to reduce both the inflammation and behavioral challenges that characterize autism in many individuals.